It is known to prepare cephalexin monohydrate (VI) using as the starting material 7-aminodesacetoxycephalosporanic acid (hereinafter 7-ADCA) which has the formula (I) ##STR1## A silylation reaction is then carried out primarily to protect the carboxy group and incidentally to protect the free amine group to form an intermediate of the formula (II) ##STR2## wherein R is hydrogen or R'.sub.3 Si and R' is lower alkyl.
The silylation step has generally been carried out in solvents such as methylene chloride which has a boiling point of 40.degree. C. at reflux, with various silylating agents in the presence of a catalyst such as saccharin. Room temperature reaction in acetonitrile has been disclosed in U.S. Pat. No. 3,694,437.
The silylated intermediate (II) is then reacted with a mixed anhydride. The mixed anhydride (IV) is made by converting D-(alpha)-phenylglycine Dane salt potassium ethyl ester (III) with pivaloyl chloride catalyzed with 2,6-lutidine in a suitable solvent.
The silylated product and the mixed anhydride are then combined in the cold to form an intermediate protected cephalexin (V) that is not isolated. This reaction is illustrated below: ##STR3## The product is then hydrolyzed to remove the silyl groups, forming cephalexin hydrochloride in solution. The hydrochloride is neutralized with a base in aqueous methanol to form the desired product, cephalexin monohydrate which has the formula (VI): ##STR4## The above process always gives incomplete reaction of 7-ADCA to cephalexin. It has a yield that is lower than desired, e.g., in the range of about 70-75%. Low yields add to the cost of producing the product. The final product is sometimes contaminated with the 7-ADCA starting material. Attempts to improve the purity of the product by altering reaction conditions, such as time, temperature, concentration of reactants, ratios of starting materials and the like have had little effect on purity. Prevention of coprecipitation of 7-ADCA with the product is difficult because 7-ADCA tends to form as an amorphous material along with the crystalline product, if the pH of a solution of both is simply raised to the isoelectric point of cephalexin. A better crystallization is done by an awkward "simultaneous" method by feeding both the acidic product solution and a caustic solution into a reservoir at a pH of 6.5-7.0 to prevent coprecipitation of the 7-ADCA. This process is cumbersome at best.
Thus a method of improving the conversion of 7-ADCA in the above general process, but without sacrificing quality of the product or adding to existing costs, would be highly desirable.